In 1893, he was appointed assistant to Rabbi Henry S. Jacobs of the Congregation B'nai Jeshurun, New York City, and later in the same year, minister to the same congregation. In 1900, he launched his career as the rabbi of Congregation Beth Israel in Portland, Oregon; typical of the activists of the Progressive Era, he attacked "many of the social and political ills of contemporary America."[1] In 1906, concerning another rabbinical appointment, Wise made a major break with the established Reform movement over the "question whether the pulpit shall be free or whether the pulpit shall not be free, and, by reason of its loss of freedom, reft of its power for good";[2] in 1907 he established his Free Synagogue, starting the "free Synagogue" movement.

Wise was a close friend of President Franklin D. Roosevelt, who turned to Wise for advice on issues concerning the Jewish community in the United States. In addition, Wise had also acted a liaison to previous President Wilson.

In 1925 Wise became chairman of Keren Hayesod, while continuing efforts to bring the Reform movement around to a pro-Zionist stance. With the rise to power of Adolf Hitler's regime, Wise took the position that public opinion in the United States and elsewhere should be rallied against the Nazis. He used his influence with President Roosevelt both in this area as well as on the Zionist question.

In 1933 while acting as honorary president of the American Jewish Congress, Wise led efforts for a Jewish Boycott of Germany. He stated "The time for prudence and caution is past. We must speak up like men. How can we ask our Christian friends to lift their voices in protest against the wrongs suffered by Jews if we keep silent? What is happening in Germany today may happen tomorrow in any other land on earth unless it is challenged and rebuked. It is not the German Jews who are being attacked. It is the Jews".[8] Urged by Wise to protest to the German government, U.S. Secretary of State Cordell Hull issued a mild statement to the American ambassador to Berlin complaining that "unfortunate incidents have indeed occurred and the whole world joins in regretting them."

Wise, along with Leo Motzkin and Nahum Goldmann, encouraged the creation in August 1936 of the World Jewish Congress in order to create a broader representative body to fight Nazism. Wise served as founding president of the World Jewish Congress president until his death in 1949. He was succeeded by his friend Nahum Goldmann.

Wise was an ardent opponent of plans to create a Jewish community in Suriname. In a letter to Keren Hayesod emissary Ida Silverman he wrote, "I personally believe, that Steinberg needs to be lynched or hanged and quartered, if that would make his lamented demise more certain." Isaac Nachman Steinberg being the co-founder of the Freeland League, a territorialist organization that was leading negotiations with the Surinamese government.[10]

In his book Holocaust Victims Accuse, Moshe Shonfeld asserts that Wise prevented the shipment of food packages from American Jews to Poland due to fear that it would be interpreted by the Allies as giving aid to the enemy.[14] This allegation is also made by historian Saul Friedländer, who writes: "In the spring of 1941 Rabbi Wise had decided to impose a complete embargo on all aid sent to Jews in occupied countries, in compliance with the U.S. government's economic boycott of the Axis powers (whereby every food package was seen as direct or indirect assistance to the enemy)... Strict orders were given to World Jewish Congress representatives in Europe to halt forthwith any shipment of packages to the ghettos, despite the fact that these packages did usually reach their destination, the Jewish Self-Help Association in Warsaw. 'All these operations with and through Poland must cease at once,' Wise cabled to Congress delegates in London and Geneva, 'and at once in English means AT ONCE, not in the future.'"[15]

Authors David Wyman and Rafael Medoff, in their book A Race Against Death: Peter Bergson, America, and the Holocaust, make a further allegation that Wise displayed a lack of leadership that hindered the Holocaust rescue attempts of others (mainly the Bergson Group's).[16] He also attempted to squelch showing and broadcast of the pageant "We Will Never Die", which sought to bring attention to the slaughter of Jews in Europe.

In a Rafael Medoff 2009 interview with Professor Benzion Netanyahu:[17] Medoff: In your view, why were American Jewish leaders so cautious during the 1940s? Netanyahu: Part of the problem was how they saw themselves. In their contacts with president Roosevelt, Jewish leaders thought of themselves as weak or helpless. Take, for example, Rabbi Stephen Wise – leader of the American Zionist movement, the American Jewish Congress and the World Jewish Congress. He thought of himself as a servant of president Roosevelt. He referred to Roosevelt as "chief", and he really meant it that way – Roosevelt was the chief, and Wise was the servant. Wise was happy to just follow along with whatever Roosevelt wanted. He was content as long as FDR just remembered his name or gave him a few minutes of his time every once in a while.[18]